Cytokines & Cells Online Pathfinder Encyclopaedia
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This cell surface antigen is known also as T90/44 antigen or Tp44. The CD28 gene contains 4 exons and maps to human 2q33-q34. CD28 is a 44 kDa homodimeric highly glycosylated protein which is expressed on most human T-cells. Almost all CD4(+) cells, approximately 50 % of the CD8(+) cells, and all CD4(-) CD8(+) cells express this marker.
The biological functions of this cell surface protein are unknown. It has been shown, however, that optimal T-cell activation and T-cell expansion requires triggering by T-cell antigen receptors and co-stimulatory signals involving crosslinking of CD28 on T-cells by its ligands expressed on antigen-presenting cells.
In T-cells activated via the T-cell receptor antibodies directed against CD28 leads to an increased synthesis and secretion of IL2, IL13, TNF-alpha, GM-CSF, IFN-gamma and TNF-beta.
CD28 is a receptor for costimulatory proteins acting on T-cells. Posttranslational processing of CD28 appears to result in variant isotypes with potentially different physiologic roles on the cell surface.
The natural ligand of CD28 is a 44-54 kDa glycoprotein, called B7 or BB1 (new designation: CD80, see also: CD antigens). B7 is a membrane glycoprotein of 262 amino acids. The original B7 (CD80) has been renamed B7-1 after the identification and cloning of a related protein, designated B7-2 (306 amino acids; designated CD86, known also as B70). The genes for B7-1 and B7-2 map to human chromosome 3q13-q23.
B7-1 is expressed primarily on activated B-cells and other antigen-presenting cells. It is expressed by macrophages, keratinocytes, T-cells, B-cells, peripheral blood dendritic and Langerhans cells. B7-2 is found on blood dendritic and Langerhans cells, B-cells, macrophages, Kupffer cells, activated monocytes and various natural killer cell clones.
Binding of B7 to CD28 on T-cells delivers a costimulatory signal that triggers T-cell proliferation by stimulating a transcription factor (see also: gene expression) that, in turn, induces the synthesis and secretion of IL2 and other cytokines. Engagement of CD28 with B7-1 stabilizes mRNA for IL2. It has been shown that CD28 engagement by B7 induces transient downregulation of CD28 synthesis and prolonged unresponsiveness to CD28 signaling.
B7 binds to another protein structurally related to CD28, called CTLA-4 (cytotoxic T-lymphocyte associated antigen 4). CTLA-4 is expressed in low copy number by T-cells only after activation, but it binds B7 with approximately 20-fold higher affinity than CD28. A soluble form of the extracellular domain of CTLA-4 has been shown to bind B7 with high avidity and to suppress T-cell dependent antibody responses in vivo. Large doses of this soluble protein also suppress responses to a second immunization.
The human gene encoding B7 has six exons, spans at least 32 kb and maps to chromosome 3q13.3-q21. Trisomy of chromosome 3 is a recurrent chromosome change seen in various lymphomas and lymphoproliferative disorders and chromosomal defects involving 3q21 have been described in leukemia and myelodysplastic states.
In vitro experiments have demonstrated that signals transduced by the CD28 receptor can determine whether the occupancy of the T-cell receptor results in a productive immune response or clonal anergy. If the costimulation by B7 is blocked, humoral responses are suppressed effectively. It has been shown that this may lead to long-term acceptance of tissue xenografts.
The CD28 antigen has been shown to bind to several intracellular proteins including phosphatidylinositol 3-kinase, growth factor receptor-bound protein-2 (GRB2; see: GRB), and the T-cell specific protein-tyrosine kinase ITK (formerly known as TSK or EMT). This binding, which proceeds through interactions with SH2 domains, also involves lck and fyn.
TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES
Saha et al (1996) have studied transgenic knock-out mice deficient in CD28 expression. These animals are completely resistant to the lethal toxic shock syndrome induced by TSST-1 (toxic shock syndrome toxin) (see: Systemic inflammatory response syndrome). Heterozygous animals are partially resistant to TSST-1.
The underlying mechanism for the resistance is a complete abrogation of TNF-alpha accumulation in the serum and a nearly complete impairment of IFN-gamma secretion in response to TSST-1 injection. CD28 costimulatory signals thus play an essential role in TSST-1 induced toxic shock syndrome.
The study of mice lacking CD28 expression has shown also that CD28 costimulation is crucial for T-cell mediated toxicity of Staphylococcal enterotoxin B.
For additional information on CD antigens see also: CD antigens MiniCOPE Dictionary.
LAST MODIFIED: 18/12/1998
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